This proposal, "Clinical and molecular studies of novel therapeutics in malignant brain tumors", builds upon my experience conducting productive, patient-oriented, neuro-oncology research and serving as the primary mentor for 9 trainees over the past 9 years at the Massachusetts General Hospital. The focus of this award is to develop improved treatment for patients with glioblastoma, a uniformly fatal cancer. The award would enable me to secure protected time and resources for research and mentoring and would enable me to expand my NIH-funded research program to develop new clinical trials of molecularly-targeted agents with novel molecular and imaging endpoints. These studies would build upon existing, funded, phase 2 trials with the goal of targeting multiple molecular pathways in glioblastoma. New research proposed in the application targets the PI3K/Akt/mTOR cell signaling pathway and the VEGFR-mediated angiogenesis cascade in an effort to improve outcome in glioblastoma patients. I have been able to establish an outstanding research environment in which to conduct these studies. Resources include a comprehensive, longitudinal, electronic IRB-approved, patient research database linked to a brain tumor tissue bank;a pipeline of novel agents from the NCI and industry;an extensive support infrastructure for clinical trials/research;an outstanding group of well-funded, productive, senior collaborators;a large brain tumor patient population;an expanding pool of talented research fellows and an institutional K12 training grant in neuro-oncology. Through better coordination of the clinical research program;more time to develop new studies with novel endpoints and more time to mentor neuro-oncology trainees this award will enhance my career as a clinical investigator, expand my grant support and enable me to produce trainee graduates who are poised to secure their own grant support for productive careers in patient-oriented neuro-oncology research.